10-119676556-T-G

Variant names:

• chr10-119676556-T-G
• rs3858339
• NM_004281.4:c.1002T>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004281.4(BAG3):​c.1002T>G​(p.Pro334Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,926 control chromosomes in the GnomAD database, including 9,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1334 hom., cov: 31)
  • Exomes 𝑓: 0.099 (8087 hom.)
• Consequence: BAG3 NM_004281.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.879

Genes affected

BAG3 (HGNC:939): (BAG cochaperone 3) BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-119676556-T-G is Benign according to our data. Variant chr10-119676556-T-G is described in ClinVar as [Benign]. Clinvar id is 44774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119676556-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.879 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.1002T>G	p.Pro334Pro	synonymous_variant	Exon 4 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.999T>G	p.Pro333Pro	synonymous_variant	Exon 4 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.1002T>G	p.Pro334Pro	synonymous_variant	Exon 4 of 4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.825T>G	p.Pro275Pro	synonymous_variant	Exon 5 of 5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18750 AN: 151934 Hom.: 1329 Cov.: 31

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.0830

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0879

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.118 AC: 29639 AN: 251464 Hom.: 2147 AF XY: 0.111 AC XY: 15118 AN XY: 135910

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.0761

Gnomad EAS exome AF: 0.266

Gnomad SAS exome AF: 0.0795

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0864

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0985 AC: 144009 AN: 1461874 Hom.: 8087 Cov.: 73 AF XY: 0.0973 AC XY: 70774 AN XY: 727240

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0810

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.0821

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.0887

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.123 AC: 18773 AN: 152052 Hom.: 1334 Cov.: 31 AF XY: 0.124 AC XY: 9218 AN XY: 74334

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.0828

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0879

Gnomad4 OTH AF: 0.129

Alfa AF: 0.0981 Hom.: 471

Bravo AF: 0.131

Asia WGS AF: 0.165 AC: 571 AN: 3478

EpiCase AF: 0.0843

EpiControl AF: 0.0836

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Mar 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro334Pro in Exon 04 of BAG3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 17.0% (637/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs3858339). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Myofibrillar myopathy 6 Benign:2

Jun 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 03, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BAG3 c.1002T>G (p.Pro334Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect biding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 13883/121360 control chromosomes (1030 homozygotes) from ExAC at a frequency of 0.1143952, which is approximately 2928 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), thus it is a common benign polymorphism. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. In literature, this variant has been reported in one patient with dilated cardiomyopathy who also carried a rare variant p.I206V and known polymorphisms c.910-21A>C and p.P407L (Ruppert_2013). Taken together, this variant is classified as benign. -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1HH Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Mar 11, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3858339; hg19: chr10-121436068; COSMIC: COSV64841630;